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A growing body of literature supports the use of intravenous iron as a compliment to erythropoiesis stimu-
latory therapy and in a signicant number of disease states where iron is necessary and oral iron is ineffec-
tive or not tolerated. The differences in efcacy, safety, and clinical nature of serious adverse events that
occur with the various iron preparations are poorly understood. Misinterpretation of adverse events leads
to underutilization of this important treatment modality. Understanding the history of the development and
use of intravenous iron is crucial to appreciate its importance in the management of anemias of dialysis,
cancer, and cancer chemotherapy and properly assess side effects and toxicity. The benets seen with
intravenous iron therapy are independent of the pretreatment levels of serum ferritin, iron, total iron binding
capacity, and percent transferrin saturation. Intravenous iron has been shown to overcome hepcidin
induced iron restricted erythropoiesis in iron-replete patients. Available clinical and experimental data
suggest that increased utilization of intravenous iron should be considered. Am. J. Hematol. 83:580588,
2008. V C 2008 Wiley-Liss, Inc.
Iron has been used by physicians throughout history. It Nonetheless, for over 50 years, recommendations for use
is believed that Sydenham, in 1681, was the rst to rec- of parenteral iron have been supported by little more than
ognize the value of iron therapy in chlorosis [1]. This im- folklore. Today, despite numerous publications to the con-
portant insight had little impact on medical practice. trary, medical students around the world are routinely
Although it was well-known at the beginning of the eight- taught that oral iron is the method of choice for replenishing
eenth century that chlorosis represented a lack of hemo- iron. Standard texts advise against the use of parenteral
globin and that iron was present in hemoglobin, it was iron unless the situation is life threatening or severe malab-
not until the nineteenth century that a French physician, sorption is present [9]. Until recently IM iron was consid-
Pierre Blaud, introduced pills containing ferrous sulfate ered the standard method of administration of parenteral
and reported the cure of chlorosis [2]. Early clinical expe- iron, despite excellent data in the Indian literature support-
rience with parenterally administered iron (intramuscularly ing IV irons superiority [10]. IM iron is painful, associated
and subcutaneously) has been summarized by Stockman with gluteal sarcomas [11,12], causes permanent discolora-
[1]. Heath et al. [3] injected subcutaneous and intramus- tion of the skin, and has never been shown to be less toxic
cular (IM) iron solutions and noted increases in hemoglo- or more efcacious than IV iron; therefore, it should be
bin levels in hypochromic anemias. The increased synthe- abandoned [13].
sis of hemoglobin was proportional to the amount of iron Prior to 1992, Imferon, manufactured by Fisons Pharma-
delivered. ceuticals in Homes Chapel England, was the only paren-
Parenteral iron usage in the early twentieth century was teral product available in the United States. The drug was
extremely limited and thought to have prohibitive toxic marketed by Merrill in the United States and was consid-
reactions. To probe the safety issue, Goetsch et al. [4] ered a minor product. In 1980, Hamstra et al. [14] pub-
introduced intravenous (IV) infusions of colloidal ferric hy- lished a review of their experience with the usage of IV iron
droxide as therapy for patients with hypochromic anemias. dextran in a cohort of approximately 500 patients with iron
Toxic reactions were severe in most instances and led to deciency and with no clinical reason to suggest that oral
the conclusion to preclude its use for therapeutic pur- administration would not be adequate. The dose and
poses except under most unusual circumstances. Subse- schedule varied from patient to patient. Virtually all patients
quent studies by Nissim [5] utilizing IV solutions of ele- achieved clinical benet. Three serious acute and eight
mental iron as saccharide led to the conclusion that delayed adverse events occurred, none of which were fatal.
parenteral iron as saccharide could be administered with All acute reactions were classied as anaphylactoid even in
relative safety and was more suitable than the ferric
hydroxide for this purpose. Clinical use of parenteral iron
accelerated with the iron saccharides in the 1940s and 1
Division of Hematology and Oncology, Private Practice Baltimore Maryland,
shortly thereafter with iron dextran. In 1954, a solution of Clinical Professor of Medicine, Georgetown University School of Medicine,
iron dextran (Imferon, Fisons pharmaceuticals) was intro- Washington, DC; 2Division of Nephrology, Professor of Medicine, Washing-
duced by Baird and Padmore [6] for the treatment of ton University School of Medicine, St. Louis, Missouri; 3Division of Hematol-
ogy and Oncology, Clinical Professor of Medicine, New York University
selective iron deciency anemias by the IM route. Used School of Medicine, Harborview VA Medical Center, New York, New York
IM and occasionally IV, in divided doses, it soon gained
acceptance as it was associated with rapid hematologic *Correspondence to: Dr. Michael Auerbach, Private Practice Baltimore Mary-
land, Clinical Professor of Medicine, Georgetown University School of Medi-
responses and a low incidence of adverse events. Since cine, Washington, DC. E-mail: mauerbachmd@aol.com
the 1990s, an upsurge in the clinical use of parenteral
Received for publication 12 October 2007; Revised 25 December 2007;
iron followed the introduction of recombinant human Accepted 2 January 2008
erythropoietin (EPO) for the correction of anemia in Am. J. Hematol. 83:580588, 2008.
patients with renal failure. Two recent papers validate the Published online 29 January 2008 in Wiley InterScience (www.interscience.
safety and efcacy of IV iron in the management of wiley.com).
patients who are iron decient [7,8]. DOI: 10.1002/ajh.21154
V
C 2008 Wiley-Liss, Inc.
the absence of tachycardia, hypotension, or respiratory dis- drate inuences the strength of the iron complex determin-
tress. Hamstra concluded that anaphylactoid reactions are ing the rate of release of bioactive iron.
serious and unpredictable and opined that IV iron dextran
should be used only when iron deciency anemia cannot Clinical use of intravenous iron
be treated adequately with oral iron. The package insert for In 1988, Auerbach et al. [17] published a study evaluating
Imferon had a black box warning about the potential for an- acute and delayed reactions in anemic patients with absence
aphylaxis and a test dose was required. of bone marrow hemosiderin receiving a total dose infusion
(TDI) of high molecular weight iron dextran (HMW ID). Doses
Parenteral iron preparations ranged from 1,000 to 3,000 mg. The total dose of iron dextran
The adverse effects of bioactive free iron resulting from was diluted in 500 ml of normal saline and infused over 412
parenteral iron administration have been recognized for hr after a test dose of the diluted solution. There was no rela-
more than 50 years. This prompted the development of for- tionship between the infusion rate and adverse event fre-
mulations that shielded iron. The currently available IV prep- quency or severity. Subsequently the more rapid rate was
arations are all ironcarbohydrate complexes or colloids recommended. One of 87 patients experienced an acute,
based on small spheroidal ironcarbohydrate particles. nonfatal, anaphylactic reaction. Approximately half of the
Each particle consists of a core made of an iron-oxyhydroxy patients developed arthralgias and myalgias within the rst
gel surrounded by a shell of carbohydrate that stabilizes the 48 hr following infusion. Premedication with aspirin and
gel, slows the release of iron, and maintains the resulting diphenhydramine had no effect on the incidence or severity of
particles in colloidal suspension [13,15]. The currently the arthralgias and myalgias. During the conduct of this study,
approved IV irons all share this structure but differ from a case report in Lancet, in 1983, of meningism [18] after a
each other by the size of the core and the identity and den- dose of IV iron led to a recall of the worlds supply of Imferon.
sity of the surrounding carbohydrate. The characteristics of A critical review of this article indicated that the patient had a
the four available preparations are listed in Table I. The mo- minor arthralgia/myalgia syndrome with headache and neck
lecular weight of the iron complex reects the size of the stiffness and recovered without residua. The subsequent
iron core and the surrounding carbohydrate. Reported mo- publication [17] recommended parenteral iron be given as a
lecular weights vary according to method of measurement. TDI, but generated little interest following the Lancet case
The strengths of the iron complex affect pharmacokinetic report and Hamstras warning about IV iron therapy. Although
characteristics of the IV irons relevant to therapeutic use. complete correction of hemoglobin decit in a subset of
The rate of release of bioactive iron is inversely related to seven of these patients with concomitant chronic inamma-
the strengths of the complex, the stronger the complex the tory disorders was an exciting and unanticipated nding, the
slower the release of the iron. The toxicological implication major inference taken from the 1988 paper by the medical
of this is that stronger complexes have a lower potential to community was the 50% incidence of arthralgias and myal-
supersaturate transferrin with subsequent free iron toxicity gias, a self-limiting harmless reaction that leaves no residua.
compared to the weaker complexes [16]. In 1998, Auerbach et al. [19] reported that 125 mg of methyl-
The different preparations all share the same metabolic prednisolone before and after TDI dramatically reduced the
fate. After IV injections, ironcarbohydrate complexes mix frequency and severity of arthralgias and myalgias (Table II).
with plasma and are phagocytosed in the reticuloendothe- As oral iron was inexpensive and nearly always effective if tol-
lial system. Within phagocytes, iron is released from the erated, physicians had little need or interest in a product,
ironcarbohydrate complex into a low molecular weight iron albeit quite safe and effective, that they had been taught and
pool. This iron is either incorporated by ferritin into intracel- believed had potentially life threatening complications.
lular iron stores or is released to the extracellular iron bind- In spite of the admonitions within the medical community
ing protein, transferrin, which delivers iron to the transferrin regarding the use of IV iron, Fisons continued marketing
receptors on the surface of erythroid precursors. The result- the product for those clinical situations where iron adminis-
ing internalization of the iron transferrin complex supplies tration as a TDI was indicated. On June 1, 1989, the FDA
iron for hemoglobin synthesis. approved recombinant human EPO for the correction of
In summary, IV iron preparations are ironcarbohydrate anemia in patients with chronic renal failure. Little did
complexes characterized by specic carbohydrates used for anyone realize the role IV iron would play in managing
complexing and shielding the iron. The specic carbohy- these patients. Amgen, the manufacturer of EPO, and the
586
Auerbach et al., 2004 Henry et al., 2007 Hedenus et al., 2007 Pinter et al., 2007 Kim et al., 2007
physiologic and rational alternative than red blood cell 19. Auerbach M, Chaudhry M, Goldman H, Ballard H. Value of methylpredniso-
lone in prevention of the arthralgia-myalgia syndrome associated with the total
transfusions [75]. IV iron is now the standard of care in ne- dose infusion of iron dextran: A double blind randomized trial. J Lab Clin Med
phrology. Antiquated and grossly incorrect notions of severe 1998;131:257260.
toxicity associated with formulations of IV iron available 20. U.S.Renal Data System. USRDS 1991 Annual Data Report. Bethesda, MD:
world-wide persist in the medical community. Newer IV iron The National Institutes of Health, National Institute of Diabetes and Digestive
and Kidney Diseases; 1991.
agents are undergoing clinical testing. Given the important 21. Mast AE, Blinder MA, Dietzen DJ. Reticulocyte hemoglobin content. Am J
role of IV iron in the treatment of various anemias and in Hematol 2007; e-pub ahead of print.
synergizing with ESAs, comparative studies of the available 22. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the anemia of end-
preparations are needed to determine their relative safety stage renal disease with recombinant human erythropoietin. Results of a
combined phase I and II clinical trial. N Engl J Med 1987;316:7378.
and efcacy. 23. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythro-
poietin doses by the use of chronic intravenous iron supplementation. Am J
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